Abstract Multiple basic science and clinical lines of evidence suggest that traumatic brain injury (TBI) is characterized by several pathologies that combine to ultimately cause neurological and cognitive deficits in those that sustain head injury. Scientists and clinicians, alike, agree that efforts to rehabilitate those suffering from TBI have been curtailed by a lack of fundamental knowledge on how co-pathology contributes to outcome. Furthermore, to date no one has tested therapies aimed at poly-trauma (i.e., treating the multiple sequelae of events that occurs following head trauma). Therefore, we seek to investigate the contribution of both vascular and neuronal injury to poor outcome following TBI. The overall hypothesis is that vascular disruption and neuronal injury synergistically contribute to poor cognitive outcome following TBI. The specific research objectives of this proposal are to 1) characterize the neuronal and vascular response to TBI, 2) determine the contribution of vascular changes and/or neuronal injury on cognitive outcome and, 3) test the effect of improving both the vascular and neurologic deficits on neurological/behavioral outcome. This proposal ultimately tests new methods to improve behavioral outcome following TBI by improving blood flow to the brain and reducing secondary neuronal injury. In doing so, we aim to develop more effective strategies to rehabilitate those that have already sustained TBI.